The clinical trial reported in 1996 by Dr. Larry Clark provided strong, human-based evidence that selenium supplementation protects against prostate cancer. Continued follow-up of Dr. Clark's study group (by JRM), continues to indicate a statistically significant, though slightly diminished, decrease in risk with selenium supplementation. While these results are encouraging, prostate cancer was only one of several endpoints considered by Dr. Clark, and the people he studied were nonmelanoma skin cancer patients living in a region with extremely low forage selenium levels. Clearly, Dr. Clark's work demands follow-up. We propose to complete our randomized clinical trial of selenium among men who, by virtue of having been diagnosed with high-grade prostatic intraepithelial neoplasia, are at substantially increased risk of prostate cancer. Each subject at baseline receives a biopsy that, to the degree practicable, minimizes the probability of undiagnosed cancer, and each subject is designated to receive a 3-year follow-up biopsy. Biopsy data is reviewed centrally by a prostate pathologist (WS), who is a leader in HGPIN research. To date, over 280 men have been registered, and 200 have been randomized toward our study goal of 465 randomizations. The primary study endpoint is PC, identified by sextant or greater prostatic biopsy. The second endpoint is toxicity, identified by patient symptom report. We have experienced difficulty obtaining sample blocks adequate for Ki-67 and TUNEL analysis of proliferation and apoptosis, respectively, but will have completed developmental evaluation of these secondary endpoint biomarkers by the end of the present study period. We intend to write a separate proposal for support of additional analyses of those markers. We propose to continue our machine vision analysis of the degradation of the basal cell layer of prostatic ducts and glands and of nuclear chromatin patterns in secretory cell nuclei. This study promises to be the largest and most methodologically rigorous to date of HGPIN, which is widely believed to be the key premalignant lesion for prostate cancer.